Clinical Therapeutics/Volume ], Number ], 2017

A Review of the Theoretical and Biological

Understanding of the Nocebo and
Placebo Phenomena
Seetal Dodd, PhD1,2,3; Olivia M. Dean, PhD1,2,4; João Vian, PhD5,6; and
Michael Berk, PhD1,2,3,4
1
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong,
Australia; 2Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia; 3The
Centre for Youth Mental Health, Parkville, Victoria, Australia; 4The Florey Institute for Neuroscience and
Mental Health, Parkville, Victoria, Australia; 5Psychiatry and Mental Health Department, Centro
Hospitalar Lisboa Norte, Lisbon, Portugal; and 6Faculdade de Medicina da Universidade de Lisboa,
Lisbon, Portugal

ABSTRACT be investigated in experimental paradigms that model

Purpose: Placebos are commonly used in experi-
mental and patient populations and are known to
influence treatment outcomes. The mechanism of
action of placebos has been investigated by several
researchers. This review investigates the current
knowledge regarding the theoretical and biological
underpinning of the nocebo and placebo phenomena.
Method: Literature was searched using PubMed
using the following keywords: nocebo, placebo,
μ-opioid, dopamine, conditioning, and expectancy.
Relevant papers were selected for review by the
authors.
Findings: The roles of conditioning and expectancy,
and characteristics associated with nocebo and
placebo responses, are discussed. These factors affect
nocebo and placebo responses, although their effect
sizes vary greatly, depending on inter-individual dif-
ferences and different experimental paradigms. The
neurobiology of the nocebo and placebo phenomena
is also reviewed, emphasizing the involvement of
reward pathways, such as the μ-opioid and dopamine
pathways. Neurobiological pathways have been
investigated in a limited range of experimental para-
digms, with the greatest efforts on experimental
models of placebo analgesia. The interconnectedness
of psychological and physiological drivers of nocebo
and placebo responses is a core feature of these
phenomena.
Implications: Further research is needed to fully
understand the underpinnings of the nocebo and
placebo phenomena. Neurobiology pathways need to
the placebo response to a broader range of patholo-
gies. Similarly, although many psychological factors
and inter-individual characteristics have been identi-
fied as significant mediators and moderators of
nocebo and placebo responses, the factors identified
to date are unlikely to be exhaustive. (Clin Ther.
2017;]:]]]–]]]) & 2017 Published by Elsevier HS
Journals, Inc.
Key words: conditioning, dopamine, expectancy,
m-opioid, nocebo, pharmacology, placebo, treatment.
For the purpose of this review, a placebo response is
an improvement in clinical symptoms when a person
is administered an inert substance, whereas a nocebo
response is a worsening of clinical symptoms or the
experiencing of treatment-emergent adverse effects. Typ-
ically, a placebo tablet is administered in control arms of
clinical trials and is manufactured to look identical to the
tablet in the active arm of a trial. Nocebo and placebo
responses are also sometimes used to describe unexpected
responses to active treatments that are not explained by
the known mechanism of action of the treatment. It may
not be possible to discern at an individual participant level
between true placebo or nocebo responses and fluctua-
tions in symptom severity due to the natural progression
of the illness; however, insightful placebo and nocebo
Accepted for publication January 5, 2017.
http://dx.doi.org/10.1016/j.clinthera.2017.01.010
0149-2918/$ - see front matter
& 2017 Published by Elsevier HS Journals, Inc.

] 2017 1
 Clinical Therapeutics
response data can often be obtained at a cohort level.
While the importance of the placebo effect is widely
understood, this is much less so for the nocebo effect. The
biological bases of the nocebo and placebo effects are only
now beginning to be unraveled. Attempts to understand
the causes of the placebo effect have increased in the last
50 years, as placebo-controlled clinical trials have become
the only accepted method for efficacy testing of new
pharmaceuticals and the problems associated with place-
bos have become more apparent. Insights have been
gained from exploring theoretical causes and influencing
factors of the effect, which have probed the mechanisms
underlying the phenomenon. This article reviews the
theoretical and biological underpinning of the nocebo
and placebo phenomena. A separate article also published
in this issue reviews the clinical importance of the nocebo
and placebo phenomena.
PSYCHOLOGICAL UNDERPINNINGS
There are a multitude of psychological elements that
have been identified as the leading factors under-
pinning the placebo and nocebo effects.
The most well-known theories pertaining to the
placebo and nocebo phenomena are the conditioning
and expectancy hypotheses. Conditioning can occur
when a person was pre-exposed to an active substance
and had a reaction that imprints in memory. When
they are then given an inert substance, they might
respond to the inert substance in the same or
similar way as they would to the active substance. A
conditioned response is a triggering of a memory loop
and, therefore, is driven by learning and adaptation.1
The effect is mediated by many variables. The
conditioning hypothesis alone is insufficient to
explain the placebo and nocebo phenomena, for
example, the extinction phenomenon in classic condi-
tioning does not necessarily occur with placebos.1
Expectancy occurs where a pre-existing belief, or
information received before being given an inert
substance (or before reporting a response2), elicits a
response to the inert substance predicated on what the
person thinks will happen. It is not necessary to have
ever been exposed to an active substance to have an
expectation of response. This may be responding to a
treatment that is not pharmacologically active because
of a pre-existing belief that the treatment either works
or might cause a specific reaction, and can be an
important factor in alternative therapies in which
2 Volume ] Number ]
pharmacologically active compounds are not included
in the treatment.3 Similarly, expectation can be a
driver of inappropriate or over-prescription of some
medications, including antibiotics, in a phenomenon
that shares much in common with the placebo effect.4
As with conditioning, expectancy also requires
learning, which may come through direct receipt of
information, suggestion, social cues, or the interaction
of all these learning modalities.5 Suggestion has also
been used experimentally to extinguish a conditioned
placebo response.6 Extinction of a conditioned
response requires learning, which in the case of a
placebo response can be facilitated by suggestion, but
may not necessarily occur solely through repeated
administration of a placebo.
Hope for improvement has also been suggested as a
driver of the placebo effect1 and this has face validity;
however, data have not been presented to support this
theory. A corollary, where despair is suggested to
drive the nocebo effect, has not been proposed in peer-
reviewed literature. However, personality traits have
been associated with placebo response,7 leaving the
possibility open to an association between personality
traits, such as optimism and pessimism, being factors
in the placebo and nocebo phenomena. However,
considerable work needs to be done to unravel
the relationship between personality and placebo
response, including expanding the theoretic under-
pinnings of the association through hypothesis-driven
research in addition to the current works that have
focused on association between personality measures
and placebo response.8 State and trait variance are a
limitation with personality measures9 and may be
relevant for the placebo response, for example,
where there is variance in dependence.
The nature of the therapeutic alliance may also be a
driver of the nocebo effect, with a hostile!dependent
relationship being an exemplar. This relationship
pattern occurs when one party is dependent on
another, and the former is hostile or mistrusting of
other people. This is a not uncommon but poorly
recognized pattern in clinical practice, where people
with insecure attachment styles are forced into trust-
ing a clinician, and their interactional style makes this
difficult Figure.
In an open-labeled study, 80 women with irritable
bowel syndrome were randomly assigned to placebo
with a persuasive rationale but without deception, or
to a control group with no treatment. Both groups
 S. Dodd et al.

Expectancy
(cortical)

µ-opioid DOPA CCK

Naloxone Proglumide
NAcc NAcc

Amy

PAG

A-Placebo B-Nocebo

Figure. Summary of regions, circuits, and neurotransmitters implicated in placebo and nocebo. A-Placebo:
Expectation activates cortical area signaling of dopamine to the nucleus accumbens and m-opioid to
the periaqueductal gray and elsewhere in the brain (the amygdala and other regions: not shown).
The placebo effect is blocked by naloxone. B-Nocebo: Negative expectation has the opposite effect
in the dopamine signaling and also activates cholecystokinin from the prefrontal cortex to the
periaqueductal gray. The nocebo effect is blocked by proglumide. Amy ¼ amygdala; CCK ¼
cholecystokinin; DOPA ¼ dopamine; NAcc ¼ nucleus accumbens; PAG ¼ periaqueductal gray.

received the same patient!provider relationship and
contact time. Participants in the placebo-treated group
had significantly higher global improvement scores.10
In this study, the placebo effect occurred even though
the participants were told they would be receiving an
inert substance “like sugar pills.” This may suggest
that the placebo effect has multiple drivers, including
expectancy, as participants were told that placebo
“has been shown to produce significant improve-
ment to [irritable bowel syndrome] symptoms,” as
well as the importance of the treatment rituals and
therapeutic environment.
There is evidence that anxiety about the tolerability
or efficacy of a treatment can be a driver of the nocebo
effect. In a meta-analysis of placebo-treated partici-
pants in clinical trials of duloxetine versus placebo,
treatment-emergent adverse events were reported
more commonly in Phase II trials, then Phase III,
and least in Phase IV.11 This suggests that a nocebo
response is more likely for a treatment that is more
experimental and uncertain compared with one that is
more established.
Choice of treatment and sense of control was found
to influence both placebo and nocebo responses in an
experiment where healthy participants (n ¼ 61) were
randomly assigned to choose between 2 equivalent
β-blocker medications or be assigned to the medications.
All study medications were actually placebos. There was
an increased placebo response in the choice group and
an increased nocebo response in the no-choice group.12
Neurobiological Findings
Numerous experiments have revealed insights into
which regions of the brain are involved in the placebo
response and which biochemical processes are occur-
ring in association with placebo and nocebo events.
Imaging studies have often used a placebo analgesia
paradigm, as it is a reliable and convenient model.
Many variation of the analgesia paradigm exist.
Placebos to replace psychotropic drugs are also a

] 2017 3
 Clinical Therapeutics
reliable and convenient paradigm, and a placebo
antidepressant has been used for at least one imaging
study. The placebo and nocebo phenomenon has been
found in numerous medical conditions, across drug
classes, and in non-pharmacologic contexts. It may be
difficult to disentangle if a neurobiological response is
applicable to the placebo and nocebo phenomena in
general or only to a specific context or as treatment
for a specific stimulus. The Figure summarizes brain
regions, circuits, and neurotransmitters implicated in
placebo and nocebo phenomena.
Neuroanatomic Regions
Studies using functional nuclear magnetic imaging
(fMRI) and positron emission tomography (PET) have
identified multiple brain regions involved in the
placebo response. Several studies and a meta-analysis
have identified the thalamus, primary and secondary
somatosensory cortex, anterior cingulate cortex
(ACC), amygdala, basal ganglia, and right lateral
prefrontal cortex as brain regions; these were less
activated when measured by fMRI, when placebo
analgesia was used to modulate a response to a pain
stimulus.5 PET studies of placebo analgesia have
identified the rostral ACC, prefrontal cortex, insula,
thalamus, amygdala, nucleus accumbens and
periaqueductal gray using a μ-opioid receptor radio-
tracers, and the basal ganglia using D2 and D3
receptor radiotracers as brain regions with neuro-
transmitter response to placebo analgesia.13
In a deceptive placebo analgesia paradigm fMRI
study for visceral pain where participants are random-
ized to receive placebo and being told the substance is
inert or placebo and being told that the substance is an
analgesic, greater modulation by placebo analgesia of
the posterior insula and dorsolateral prefrontal cortex
was observed in women compared with men,
although the efficacy of placebo analgesia in control-
ling expected or perceived pain did not differ between
sexes.14 A deceptive placebo analgesia paradigm fMRI
study for noxious heat pain, where placebos were
labeled as a popular branded original or a generic
analgesic, original branded and generic labeled
placebos were both associated with activation of the
anterior insulae at baseline and activation of the
dorsomedial prefrontal cortex after the interventions.
Greater activation of the bilateral dorsolateral (as well
as dorsomedial) prefrontal cortex (PFC) was observed
for the placebo labeled as the original brand. The
4 Volume ] Number ]
placebo labeled as the original brand was also
associated with decreased pain intensity compared
with the generic-labeled placebo.15 A recent PET
study using a μ-opioid receptor radiotracer, patients
with major depressive disorder were treated with
placebo in a crossover study in which one placebo
was labeled “active” and the other “inactive,” and
told that the active treatment was a fast-acting anti-
depressant and the inactive treatment was a control.
Active treatment was superior to inactive treatment for
placebo-induced opioid release in brain regions sub-
genual ACC, nucleus accumbens, amygdala, thalamus,
and hypothalamus.16 Placebo activation of endogenous
opioid neurotransmitters that bind to receptors in the
pregenual and subgenual rostral ACC, the dorsolateral
PFC, the insular cortex, and the nucleus accumbens,
has also been observed in an analgesia paradigm using
PET.17 Substantial inter-individual variation has been
reported for brain regions involved in placebo response
to expectations of analgesia.18
An fMRI study of 24 healthy adults investigated
neural activation in response to stimuli associated
with different expectations. In 3 separate sessions (ie,
training, conditioning, and scanning sessions) on
different days, participants were subject to 12-second
heat pain stimulus to their right forearm. At the
conditioning and training sessions, participants skin
was treated with an inert cream before the heat pain
stimulus. One cream was labeled “lidocaine” (positive
expectancy), one was labeled “neutral,” and the third
cream was labeled “capsaicin” (negative expectancy).
Difference between positive and negative expectancy
conditions were observed, either pre or post stimulus,
in the dorsal ACC, right orbito-PFC, anterior insula,
right dorsolateral PFC, left ventral striatum,
orbitofrontal cortex, periaqueductal gray, and left
operculum and putamen.19 This experiment found
that placebo and nocebo expectancies have effects
on different brain networks in response to a pain
stimulus.
There are limitations to using fMRI and PET to study
models of the nocebo and placebo effects. Firstly, most
experiments are conducted on health volunteers, so
important drivers of the placebo response, such as hope
and therapeutic alliance, are not included in the exper-
imental construct. Secondly, study participants are inside
a large piece of medical equipment, which is a specific
experimental environment. Thirdly, the experimental
environment limits the study design and duration.

Neurochemical Processes
The placebo response has been associated with the
release of endorphins and dopamine, providing a neuro-
chemical explanation of the efficacy of placebo analge-
sia.13 Early evidence of the elevation of endogenous
opioids in placebo analgesia was reported in 1978, when
Levine et al20 used placebo as an analgesic for dental
postoperative pain and reversed the analgesic effects by
administering the opiate antagonist naloxone.
Endorphin and dopamine release and opioid and
dopamine receptors are widely distributed, but are also
clustered in specific brain regions that correspond with
many of the regions identified by fMRI studies. There
are 3 major types of opioid receptor, μ-opioid receptor,
δ-opioid receptor, and κ-opioid receptor, which can be
further divided into subtypes, and a fourth nociception
or orphanin receptor.21 These receptors are widely
distributed through the brain and other organs, but
with differences in expression and distribution.21 Opioid
receptors have a range of functions, including pain
modulation and their association with analgesia,
however, they are also associated with various
functions, including mood regulation, homeostasis, cell
proliferation, and neuroprotection.21
Much placebo neurobiological research has focused
on analgesia, often investigating the μ-opioid receptor.
Where major depressive disorder has been investi-
gated16 increased μ-opioid neurotransmission has
been observed, similar to observations in analgesia
research, which may suggest similarities to, or be a
consequence of, using a similar research method.
Inter-individual variation in μ-opioid neurotransmis-
sion has also been observed in a study of 50 healthy
controls with and without placebo administration,
where psychological trait scores measured with scales
for altruism, straightforwardness, and angry hostility
accounted for 25% of the variance in placebo analge-
sic response and also found that participants scoring
above the median in a composite score of all 3 traits
had increased μ-opioid neurotransmission in response
to placebo administration.22
An experiment where hypertonic saline was injected
into the masseter muscle of 20 healthy individuals to
induce pain, with or without placebo analgesia,
was investigated using PET to examine changes in
dopamine and opioid neurotransmission. The study
used [C11]-labeled raclopride (selective for D2 recep-
tors) and carfentanil (selective for μ-opioid receptors).
Participants were asked to rate the efficacy of the
] 2017
S. Dodd et al.
analgesic and describe adverse events. Effective placebo
analgesia was associated with increased dopamine and
opioid neurotransmission in multiple brain regions. A
nocebo effect was identified in 5 participants who
reported increased pain intensity during placebo ad-
ministration. Nocebo responders showed decreased
dopamine and opioid neurotransmission in the same
brain regions where increased neurotransmission was
observed in placebo responders.23
In a study where patients reporting mild perioperative
pain were given saline solution and were told that the
solution produced an increased pain (nocebo hyperanal-
gesia), pain was abolished when proglumide was added
to the solution. Proglumide is a cholecystokinin antago-
nist, which blocks both the CCKA and CCKB receptor
subtypes, suggesting that nocebo hyperanalgesia is medi-
ated at least in part by cholecystokinin.24
PET studies have found that administration of a
placebo to people with Parkinson’s disease can induce
dopamine release in the striatum.25 Furthermore, in a
study of 24 participants with Parkinson’s disease
undergoing deep brain stimulation, the firing rate of
selected neurons was changed in participants who
showed a clinical response to placebo, but not in
nonresponders or partial responders to placebo. Mean
firing frequency decreased in subthalamic and substantia
nigra pars reticulata neurons and increased in ventral
anterior and anterior ventral lateral thalamus neurons.
The placebo effect had a duration of no more than 45
minutes. Other parts of the brain circuitry were not
measured.26 Another study found that placebo was
enhanced with preconditioning by apomorphine
exposure, with the greater number of exposures to
apomorphine associated with a greater change in
neuronal firing rates.27
Endocannabinoids have a role in placebo-induced
analgesia, as reported in a study analogous to the
1978 naloxone experiment that reported on the role
of endorphins.20 Placebo was effective as an analgesic
against tourniquet pain after preconditioning
participants to analgesia with either the opioid
morphine or the nonsteroidal anti-inflammatory drug
ketorolac. In these preconditioned participants, the
CB1 cannabinoid receptor antagonist rimonabant
reversed placebo analgesia after preconditioning with
ketorolac, but did not reverse placebo analgesia in
participants preconditioned with morphine.28
Prostaglandin levels have also been found to
change in response to placebo. In an experiment,
5
 Clinical Therapeutics
placebo was used to treat headache caused by high-
altitude (3,500 m) hypobaric hypoxia, after precondi-
tioning by treating headache with inhaled oxygen and
later giving placebo (sham) oxygen, or by precondi-
tioning with aspirin and later giving a placebo tablet.
In both scenarios, the placebos were effective for
reducing headache pain, but the analgesic effect of
placebo oxygen was superior to placebo aspirin.
Placebo oxygen was found to specifically reduce
salivary prostaglandin E2, mimicking the therapeutic
pathway of oxygen therapy, whereas placebo aspirin
had a more general effect on prostaglandin synthesis,
mimicking the effect of cyclooxygenase inhibition.29
Interaction of Psychological and Physiological
Factors
Placebo and nocebo responses occur within a psycho-
logical and physiological context. This context is critical
for all aspects of the response, including the neuro-
biological elements. The context includes characteristics
of the study or treatment in which the placebo or nocebo
effect is observed and characteristics of the study partic-
ipant or patient, as well as other characteristics, including
the environment in which the study or treatment is being
conducted. The doctor!patient relationship, for example,
can include trust, where untrustworthiness has been
associated with increased amygdala activity, and trust-
worthiness can be modulated by oxytocin.30 Trust may
be a characteristic not only of the active relationship,
but is powerfully influenced by personality and
developmental factors that set individuals levels of trust.
Similarly, hope and hopelessness have been associated
with serotonergic and noradrenergic systems,30 showing
the potential for variables relevant to placebo having a
direct effect on neurotransmitter systems directly
implicated in mood. Also relevant to the placebo
response, admiration and compassion by a participant
have been found through fMRI to result in a pattern of
activation within the posteromedial cortice.31 Learned
helplessness has been found to effect serotonin
regulation.32 The relationship between pain and stress
and anxiety with the hypothalamic!pituitary!adrenal
axis and cortisol is well established.33
Negative and positive expectations, which are sug-
gested to be major drivers of the placebo and nocebo
responses, have been found to induce changes in reward
circuitry in the nucleus accumbens, and similarly, con-
ditioning may induce changes in learning mechanisms.30
6 Volume ] Number ]
DISCUSSION
The drivers of the placebo and nocebo phenomena may
be a synergy of multiple biological and psychological
variables, mediated by a further multitude of contextual
and individual variables. There is clear evidence of
physiological factors that underpin the phenomena, as
well as a contribution by psychological factors. This is
further complicated by considerable inter-individual
differences. Although there is consistency in the literature
in terms of which pathways are implicated in placebo
and nocebo responses, neurotransmitter activation does
not occur with all individuals experiencing the same
stimulus. Factors such as conditioning, expectancy, hope
and despair, wanting to please the experimenters, treat-
ment setting, caring nature of the clinician, and personal
beliefs about medications, all play a role.
Furthermore, while the placebo and nocebo effect has
been observed for treatment for a broad range of medical
conditions, it has only been carefully studied in exper-
imental models of a narrow range of conditions, espe-
cially pain and analgesia. It is possible, or even likely, that
the neural pathways involved in a placebo analgesia
response are different, or only partly overlapping, from
the neural pathways involved in a placebo response for a
different treatment. The investigation of the biological
and theoretical underpinning of the placebo and nocebo
phenomena is at an early stage and much additional
research is required.
ACKNOWLEDGMENTS
Michael Berk is supported by a National Health
and Medical Research Council Senior Principal
Research Fellowship 1059660. All authors contrib-
uted to preparing the paper and gave final consent for
publication. SD wrote the first draft. OMD and MB
extended the draft and edited the full manuscript. JV
prepared the figure and edited the full manuscript.
CONFLICTS OF INTEREST
SD has received grant support from the Stanley Medical
Research Institute, NHMRC, Beyond Blue, ARHRF,
Simons Foundation, Geelong Medical Research Founda-
tion, Fondation FondaMental, Eli Lilly, Glaxo SmithKline,
Organon, Mayne Pharma and Servier, speaker’s fees from
Eli Lilly, advisory board fees from Eli Lilly and Novartis
and conference travel support from Servier. OMD has
received grant support from the Brain and Behavior
Foundation, Simons Autism Foundation, Stanley Medical

Research Institute, Deakin University, Lilly, NHMRC and
Australasian
Society for Bipolar and Depressive Disorders (ASBDD)/
Servier. JV has no conflicts of interest. MB has received
Grant/Research Support from the NIH, Cooperative
Research Centre, Simons Autism Foundation, Cancer
Council of Victoria, Stanley Medical Research Founda-
tion, MBF, NHMRC, Beyond Blue, Rotary Health,
Geelong Medical Research Foundation, Bristol Myers
Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock
Board, Organon, Novartis, Mayne Pharma, Servier,
Woolworths, Avant and the Harry Windsor Foundation,
has been a speaker for Astra Zeneca, Bristol Myers
Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lund-
beck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay
and Wyeth, and served as a consultant to Allergan, Astra
Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal
Development, Eli Lilly, Glaxo SmithKline, Janssen Cilag,
Lundbeck Merck, Pfizer and Servier. He is a co-inventors
of two provisional patents regarding the use of NAC and
related compounds for psychiatric indications, which,
while assigned to the Mental Health Research Institute,
could lead to personal remuneration upon a commercial-
ization event.
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Address correspondence to: Seetal Dodd, PhD, PO Box 281, Geelong,
Victoria 3220, Australia. E-mail: seetald@barwonhealth.org.au

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